Literature Review: Investigating Drug Transport at the Blood-Brain Barrier and the Effects of P-glycoprotein on the Brain Distribution of Drugs.

The blood-brain barrier (BBB) is a unique barrier that strictly regulates the entry of endogenous substrates and xenobiotics into the brain. This is due to its tight junctions and the array of transporters and metabolic enzymes that are expressed. The determination of brain concentrations in vivo is difficult, laborious and expensive which means that there is interest in developing predictive tools of brain distribution. Predicting brain concentrations is important even in early drug development to ensure efficacy of central nervous system (CNS) targeted drugs and safety of non-CNS drugs. The literature review covers the most common current in vitro, in vivo and in silico methods of studying transport into the brain, concentrating on transporter effects. The consequences of efflux mediated by p-glycoprotein, the most widely characterized transporter expressed at the BBB, is also discussed. The aim of the experimental study was to build a pharmacokinetic (PK) model to describe p-glycoprotein substrate drug concentrations in the brain using commonly measured in vivo parameters of brain distribution. The possibility of replacing in vivo parameter values with their in vitro counterparts was also studied. All data for the study was taken from the literature. A simple 2-compartment PK model was built using the Stella™ software. Brain concentrations of morphine, loperamide and quinidine were simulated and compared with published studies. Correlation of in vitro measured efflux ratio (ER) from different studies was evaluated in addition to studying correlation between in vitro and in vivo measured ER. A Stella™ model was also constructed to simulate an in vitro transcellular monolayer experiment, to study the sensitivity of measured ER to changes in passive permeability and Michaelis-Menten kinetic parameter values. Interspecies differences in rats and mice were investigated with regards to brain permeability and drug binding in brain tissue. Although the PK brain model was able to capture the concentration-time profiles for all 3 compounds in both brain and plasma and performed fairly well for morphine, for quinidine it underestimated and for loperamide it overestimated brain concentrations. Because the ratio of concentrations in brain and blood is dependent on the ER, it is suggested that the variable values cited for this parameter and its inaccuracy could be one explanation for the failure of predictions. Validation of the model with more compounds is needed to draw further conclusions. In vitro ER showed variable correlation between studies, indicating variability due to experimental factors such as test concentration, but overall differences were small. Good correlation between in vitro and in vivo ER at low concentrations supports the possibility of using of in vitro ER in the PK model. The in vitro simulation illustrated that in the simulation setting, efflux is significant only with low passive permeability, which highlights the fact that the cell model used to measure ER must have low enough paracellular permeability to correctly mimic the in vivo situation.

Seismic bearing capacity factors for spread foundations

The effect of horizontal earthquake body forces on the bearing capacity of foundations has been examined computationally in a rigorous manner by employing the method of stress characteristics. The bearing capacity factors N-c, N-q and N-y, due to the components of soil cohesion, ground surcharge pressure and soil unit weight respectively, have been plotted as a function of earthquake acceleration coefficient (a(h)) for different values of soil friction angle (phi). The inclusion of earthquake body forces causes a considerable reduction in the bearing capacity factors. The bearing capacity factors N-c and N-q are seen to be approximately of the same magnitude as those reported in the literature on the basis of different solution methods. However, the obtained values of N-y are found to be significantly smaller than the available results. The nature of the pressure distribution along the footing base and the geometry of the observed failure patterns vary with the consideration of earthquake body forces.

Bimodal distribution of motility and cell fate in Dictyostelium discoideum

Pre-starvation amoebae of Dictyostelium discoideum exhibit random movements. Starved cells aggregate by directed movements (chemotaxis) towards cyclic AMP and differentiate into live spores or dead stalk cells. Many differences between presumptive spore and stalk cells precede differentiation. We have examined whether cell motility-related factors are also among them. Cell speeds and localisation of motility-related signalling molecules were monitored by live cell imaging and immunostaining (a) in nutrient medium during growth, (b) immediately following transfer to starvation medium and (c) in nutrient medium that was re-introduced after a brief period of starvation. Cells moved randomly under all three conditions but mean speeds increased following transfer from nutrient medium to starvation medium; the transition occurred within 15 min. The distribution of speeds in starvation medium was bimodal: about 20% of the cells moved significantly faster than the remaining 80%. The motility-related molecules F-actin, PTEN and PI3 kinase were distributed differently in slow and fast cells. Among starved cells, the calcium content of slower cells was lower than that of the faster cells. All differences reverted within 15 min after restoration of the nutrient medium. The slow/fast distinction was missing in Polysphondylium pallidum, a cellular slime mould that lacks the presumptive stalk and spore cell classes, and in the trishanku (triA(center dot)) mutant of D. discoideum, in which the classes exist but are unstable. The transition from growth to starvation triggers a spontaneous and reversible switch in the distribution of D. discoideum cell speeds. Cells whose calcium content is relatively low (known to be presumptive spore cells) move slower than those whose calcium levels are higher (known to be presumptive stalk cells). Slow and fast cells show different distributions of motility-related proteins. The switch is indicative of a bistable mechanism underlying cell motility.

Clonal complexes and virulence factors of Staphylococcus aureus from several cities in India

Background: Diseases from Staphylococcus aureus are a major problem in Indian hospitals and recent studies point to infiltration of community associated methicillin resistant S. aureus (CA-MRSA) into hospitals. Although CA-MRSA are genetically different from nosocomial MRSA, the distinction between the two groups is blurring as CA-MRSA are showing multidrug resistance and are endemic in many hospitals. Our survey of samples collected from Indian hospitals between 2004 and 2006 had shown mainly hospital associated methicillin resistant Staphylococcus aureus (HA-MRSA) carrying staphylococcal cassette chromosome mec (SCCmec) type III and IIIA. But S. aureus isolates collected from 2007 onwards from community and hospital settings in India have shown SCCmec type IV and V cassettes while several variations of type IV SCCmec cassettes from IVa to IVj have been found in other parts of the world. In the present study, we have collected nasal swabs from rural and urban healthy carriers and pus, blood etc from in patients from hospitals to study the distribution of SCCmec elements and sequence types (STs) in the community and hospital environment. We performed molecular characterization of all the isolates to determine their lineage and microarray of select isolates from each sequence type to analyze their toxins, virulence and immune-evasion factors. Results: Molecular analyses of 68 S. aureus isolates from in and around Bengaluru and three other Indian cities have been carried out. The chosen isolates fall into fifteen STs with all major clonal complexes (CC) present along with some minor ones. The dominant MRSA clones are ST22 and ST772 among healthy carriers and patients. We are reporting three novel clones, two methicillin sensitive S. aureus (MSSA) isolates belonging to ST291 (related to ST398 which is live stock associated), and two MRSA clones, ST1208 (CC8), and ST672 as emerging clones in this study for the first time. Sixty nine percent of isolates carry Panton-Valentine Leucocidin genes (PVL) along with many other toxins. There is more diversity of STs among methicillin sensitive S. aureus than resistant ones. Microarray analysis of isolates belonging to different STs gives an insight into major toxins, virulence factors, adhesion and immune evasion factors present among the isolates in various parts of India. Conclusions: S. aureus isolates reported in this study belong to a highly diverse group of STs and CC and we are reporting several new STs which have not been reported earlier along with factors influencing virulence and host pathogen interactions.

Fish distribution dynamics in the Aghanashini estuary of Uttara Kannada, west coast of India

Fish diversity (77 species) in the Aghanashini River estuary of the Indian west coast is linked to variable salinity conditions and zones I, II and III for high, medium and low salinity respectively. Zone I, the junction between Arabian Sea and the estuary, had all species in yearly succession due to freshwater conditions in monsoon to high salinity in pre-monsoon. The medium (zone II) and low (zone III) salinity mid and upstream portions had maximum of 67 and 39 fish species respectively. Maintenance of natural salinity regimes in estuary, among other ecological factors, is critical for its fish diversity.

A Computational Study of the Factors Influencing the PVC-Triggering Ability of a Cluster of Early Afterdepolarization-Capable Myocytes

Premature ventricular complexes (PVCs), which are abnormal impulse propagations in cardiac tissue, can develop because of various reasons including early afterdepolarizations (EADs). We show how a cluster of EAD-generating cells (EAD clump) can lead to PVCs in a model of cardiac tissue, and also investigate the factors that assist such clumps in triggering PVCs. In particular, we study, through computer simulations, the effects of the following factors on the PVC-triggering ability of an EAD clump: (1) the repolarization reserve (RR) of the EAD cells; (2) the size of the EAD clump; (3) the coupling strength between the EAD cells in the clump; and (4) the presence of fibroblasts in the EAD clump. We find that, although a low value of RR is necessary to generate EADs and hence PVCs, a very low value of RR leads to low-amplitude EAD oscillations that decay with time and do not lead to PVCs. We demonstrate that a certain threshold size of the EAD clump, or a reduction in the coupling strength between the EAD cells, in the clump, is required to trigger PVCs. We illustrate how randomly distributed inexcitable obstacles, which we use to model collagen deposits, affect PVC-triggering by an EAD clump. We show that the gap-junctional coupling of fibroblasts with myocytes can either assist or impede the PVC-triggering ability of an EAD clump, depending on the resting membrane potential of the fibroblasts and the coupling strength between the myocyte and fibroblasts. We also find that the triggering of PVCs by an EAD clump depends sensitively on factors like the pacing cycle length and the distribution pattern of the fibroblasts.

Stress intensity factors for functionally graded solid cylinders

This paper presents the mode I stress intensity factors for functionally graded solid cylinders with an embedded penny-shaped crack or an external circumferential crack. The solid cylinders are assumed under remote uniform tension. The multiple isoparametric finite element method is used. Various types of functionally graded materials and different gradient compositions for each type are investigated. The results show that the material property distribution has a quite considerable in influence on the stress intensity factors. The influence for embedded cracks is quite different from that for external cracks.

Elastodynamic stress-intensity factors for a semiinfinite crack under 3-d combined mode loading

The dynamic stress intensity factor histories for a half plane crack in an otherwise unbounded elastic body are analyzed. The crack is subjected to a traction distribution consisting of two pairs of suddenly-applied shear point loads, at a distance L away from the crack tip. The exact expression for the combined mode stress intensity factors as the function of time and position along the crack edge is obtained. The method of solution is based on the direct application of integral transforms together with the Wiener-Hopf technique and the Cagniard-de Hoop method, which were previously believed to be inappropriate. Some features of solutions are discussed and the results are displayed in several figures.

Regulation of Energy Metabolism by the Extracytoplasmic Function (ECF) σ Factors of Arcobacter butzleri

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Factors to consider when using native biological control organisms to manage exotic plants

Biological control of exotic plant populations with native organisms appears to be increasing, even though its success to date has been limited. Although many researchers and managers feel that native organisms are easier to use and present less risk to the environment this may not be true. Developing a successful management program with a native insect is dependent on a number of critical factors that need to be considered. Information is needed on the feeding preference of the agent, agent effectiveness, environmental regulation of the agent, unique requirements of the agent, population maintenance of the agent, and time to desired impact. By understanding these factors, researchers and managers can develop a detailed protocol for using the native biological control agent for a specific target plant. . We found E. lecontei in 14 waterbodies, most of which were in eastern Washington. Only one lake with weevils was located in western Washington. Weevils were associated with both Eurasian ( Myriophyllum spicatum L.) and northern watermilfoil ( M. sibiricum K.). Waterbodies with E. lecontei had significantly higher ( P < 0.05) pH (8.7 ± 0.2) (mean ± 2SE), specific conductance (0.3 ± 0.08 mS cm -1 ) and total alkalinity (132.4 ± 30.8 mg CaCO 3 L -1 ). We also found that weevil presence was related to surface water temperature and waterbody location ( = 24.3, P ≤ 0.001) and of all the models tested, this model provided the best fit (Hosmer- Lemeshow goodness-of-fit = 4.0, P = 0.9). Our results suggest that in Washington State E. lecontei occurs primarily in eastern Washington in waterbodies with pH ≥ 8.2 and specific conductance ≥ 0.2 mS cm -1 . Furthermore, weevil distribution appears to be correlated with waterbody location (eastern versus western Washington) and surface water temperature.

The distribution of ctenophora in the Patuxent estuary during the summer of 1958

Investigation of Ctenophores in the Chesapeake Bay area, includes some aspects of their life history, growth, reproduction, feeding and food habits, abundance and distribution. the purpose of the entire project is to supplement and add to the biological knowledge and understanding of ctenophores as a group and of the several individual species found int he area to be studied. Includes possible factors involved and implications also being looked at. (PDF contains 33 pages)

Factors associated with chronic pain in patients with bipolar depression: a cross-sectional study

Background: While pain is frequently associated with unipolar depression, few studies have investigated the link between pain and bipolar depression. In the present study we estimated the prevalence and characteristics of pain among patients with bipolar depression treated by psychiatrists in their regular clinical practice. The study was designed to identify factors associated with the manifestation of pain in these patients.- Methods:Patients diagnosed with bipolar disorder (n=121) were selected to participate in a cross-sectional study in which DSM-IV-TR criteria were employed to identify depressive episodes. The patients were asked to describe any pain experienced during the study, and in the 6 weeks beforehand, by means of a Visual Analogical Scale (VAS).- Results: Over half of the bipolar depressed patients (51.2%, 95% CI: 41.9%–60.6%), and 2/3 of the female experienced concomitant pain. The pain was of moderate to severe intensity and prolonged duration, and it occurred at multiple sites, significantly limiting the patient’s everyday activities. The most important factors associated with the presence of pain were older age, sleep disorders and delayed diagnosis of bipolar disorder.- Conclusions: Chronic pain is common in bipolar depressed patients, and it is related to sleep disorders and delayed diagnosis of their disorder. More attention should be paid to study the presence of pain in bipolar depressed patients, in order to achieve more accurate diagnoses and to provide better treatment options.

Seasonal, horizontal, and vertical distribution of phytoplankton chlorophyll a in the Northeast U.S. Continental Shelf Ecosystem

The broad scale features in the horizontal, vertical, and seasonal distribution of phytoplankton chlorophyll a on the northeast U.S. continental shelf are described based on 57,088 measurements made during 78 oceanographic surveys from 1977 through 1988. Highest mean water column chlorophyll concentration (Chlw,) is usually observed in nearshore areas adjacent to the mouths of the estuaries in the Middle Atlantic Bight (MAB), over the shallow water on Georges Bank, and a small area sampled along the southeast edge of Nantucket Shoals. Lowest Chlw «0.125 ug l-1) is usually restricted to the most seaward stations sampled along the shelf-break and the central deep waters in the Gulf of Maine. There is at least a twofold seasonal variation in phytoplankton biomass in all areas, with highest phytoplankton concentrations (m3) and highest integrated standing stocks (m2) occurring during the winter-spring (WS) bloom, and the lowest during summer, when vertical density stratification is maximal. In most regions, a secondary phytoplankton biomass pulse is evident during convective destratification in fall, usually in October. Fall bloom in some areas of Georges Bank approaches the magnitude of the WS-bloom, but Georges Bank and Middle Atlantic Bight fall blooms are clearly subordinate to WS-blooms. Measurements of chlorophyll in two size-fractions of the phytoplankton, netplankton (>20 um) and nanoplankton «20 um), revealed that the smaller nanoplankton are responsible for most of the phytoplankton biomass on the northeast U.S. shelf. Netplankton tend to be more abundant in nearshore areas of the MAB and shallow water on Georges Bank, where chlorophyll a is usually high; nanoplankton dominate deeper water at the shelf-break and deep water in the Gulf of Maine, where Chlw is usually low. As a general rule, the percent of phytoplankton in the netplankton size-fraction increases with increasing depth below surface and decreases proceeding offshore. There are distinct seasonal and regional patterns in the vertical distribution of chlorophyll a and percent netplankton, as revealed in composite vertical profiles of chlorophyll a constructed for 11 layers of the water column. Subsurface chlorophyll a maxima are ubiquitous during summer in stratified water. Chlorophyll a in the subsurface maximum layer is generally 2-8 times the concentration in the overlying and underlying water and approaches 50 to 75% of the levels observed in surface water during WS-bloom. The distribution of the ratio of the subsurface maximum chlorophyll a to surface chlorophyll a (SSR) during summer parallels the shelfwide pattern for stability, indexed as the difference in density (sigma-t) between 40 m and surface (stability 40. The weakest stability and lowest SSR's are found in shallow tidally-mixed water on Georges Bank; the greatest stability and highest SSR's (8-12:1) are along the mid and outer MAB shelf, over the winter residual water known as the "cold band." On Georges Bank, the distribution of SSR and the stability40 are roughly congruent with the pattern for maximum surface tidal current velocity, with values above 50 cms-1 defining SSR's less than 2:1 and the well-mixed area. Physical factors (bathymetry, vertical mixing by strong tidal currents, and seasonal and regional differences in the intensity and duration of vertical stratification) appear to explain much of the variability in phytoplankton chlorophyll a throughout this ecosystem. (PDF file contains 126 pages.)

Distribution of catch-per-unit-of-effort and fishing effort for tuna in the Eastern Tropical Pacific Ocean by months of the year 1951-1960

ENGLISH: Comparison of physical and biological environmental factors affecting the aggregation of tunas with the success of fishing by the commercial fleets, requires that catch and effort data be examined in greater detail than has been presented in these publications. Consequently, the United States Bureau of Commercial Fisheries Biological Laboratory, San Diego, to serve the needs of its program of research on causes of variations in tuna abundance, made arrangements with the Tuna Commission to summarize these catch and effort data by month, by one-degree area, by fishing vessel size-class, for the years 1951-1960 for bait boats and 1953-1960 for purse-seiners. The present paper describes the techniques employed in summarizing these data by automatic data processing methods. It also presents the catch and effort information by months, by five-degree areas and certain combinations of five-degree areas for use by fishermen, industry personnel, and research agencies. Because of space limitations and other considerations, the one-degree tabulations are not included but are available at the Tuna Commission and Bureau laboratories. SPANISH: La comparación de los factores ambientales físicos y biológicos que afectan la agrupación del atún, con el éxito obtenido en la pesca por las flotas comerciales, requiere que los datos sobre la captura y el esfuerzo sean examinados con mayor detalle de lo que han sido presentados en estas publicaciones. En consecuencia, el Laboratorio Biológico del Buró de Pesquerías Comerciales de los Estados Unidos, situado en San Diego, a fin de llenar los requisitos de su programa de investigación sobre las causas de las variaciones en la abundancia del atún, hizo arreglos con la Comisión del Atún para sumarizar esos datos sobre la captura y el esfuerzo por meses, por áreas de un grado, por clases de tamaño de las embarcaciones de pesca durante los años 1951-1960 en lo que concierne a los barcos de carnada y durante el período 1953-1960 en lo que respecta a los barcos rederos. El presente trabajo describe la técnica empleada en la sumarización de dichos datos mediante métodos automáticos de manejo de datos. También se da aquí la información sobre la captura y el esfuerzo por meses, por áreas de cinco grados y ciertas combinaciones de áreas de cinco grados para el uso de los pescadores, del personal de la industria y de las oficinas de investigación. Por falta de espacio y otras razones, las tabulaciones de las áreas de un grado no han sido incluídos en este trabajo, pero están a la disposición de quien tenga interés en los laboratorios de la Comisión del Atún y del Buró.

Intranasal Delivery of Plasma and Platelet Growth Factors Using PRGF-Endoret System Enhances Neurogenesis in a Mouse Model of Alzheimer’s Disease

[EN] Neurodegeneration together with a reduction in neurogenesis are cardinal features of Alzheimer’s disease (AD) induced by a combination of toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with diverse neurotrophins in experimental therapeutic approaches. The aim of this study was to investigate whether intranasal delivery of plasma rich in growth factors (PRGF-Endoret), an autologous pool of morphogens and proteins, could enhance hippocampal neurogenesis and reduce neurodegeneration in an amyloid precursor protein/presenilin-1 (APP/PS1) mouse model. Neurotrophic and neuroprotective actions were firstly evident in primary neuronal cultures, where cell proliferation and survival were augmented by Endoret treatment. Translation of these effects in vivo was assessed in wild type and APP/PS1 mice, where neurogenesis was evaluated using 5-bromodeoxyuridine (BdrU), doublecortin (DCX), and NeuN immunostaining 5 weeks after Endoret administration. The number of BrdU, DCX, and NeuN positive cell was increased after chronic treatment. The number of degenerating neurons, detected with fluoro Jade-B staining was reduced in Endoret-treated APP/PS1 mice at 5 week after intranasal administration. In conclusion, Endoret was able to activate neuronal progenitor cells, enhancing hippocampal neurogenesis, and to reduce Aβ-induced neurodegeneration in a mouse model of AD.